According to the National Cancer Institute approximately 220,800 cases of prostate cancer will be diagnosed in 2015, with over 27,540 cases proving to be lethal (about 12.5%) (Institute, N. C. Cancer Statistics (2015)). Existing imaging techniques for detection and therapeutic monitoring of prostate cancer are inadequate for effective management of the disease. The transmembrane glycoprotein prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for both imaging and therapy of prostate cancer (Afshar-Oromieh et al. (2014) Eur J Nucl Med Mol Imaging; Afshar-Oromieh et al., (2013) Eur J Nucl Med Mol Imaging 40, 486-95). PSMA is found in benign, as well as in malignant prostate tissue (Murphy et al., (1995) Prostate 26, 164-8; Murphy et al., (1998) Urology 51, 89-97; Murphy et al., (1998) J Urol 160, 2396-401). However, expression of PSMA is greatest in prostate adenocarcinoma, particularly in castration-resistant disease (Sweat et al. (1998) Urology 52, 637-40; Silver et al. (1997) Clin Cancer Res 3, 81-5). PSMA is also present in the neovasculature of solid tumors including kidney, lung (Wang et al. (2015) PLoS ONE 10.), stomach, colon, and breast (Haffner et al. (2009) Hum Pathol 40, 1754-61; Haffner et al (2012) Mod Pathol 25, 1079-85; Baccala et al. (2007) Urology 70, 385-90). Expression of PSMA is associated with the neovascular endothelium in non-prostate tumors (Chang et al. (1999) Mol Urol 3, 313-320; Chang et al. (1999) Clin Cancer Res 5, 2674-81).
PSMA-targeted agents to image patients with prostate cancer using positron emission tomography (PET) have been reported by several groups (Cho et al. (2012) J Nucl Med 53, 1883-91; Afshar-Oromieh et al. (2012) Eur J Nucl Med Mol Imaging 39, 1085-6; Afshar-Oromieh et al. (2013) Eur J Nucl Med Mol Imaging 40, 1629-30; Afshar-Oromieh et al. (2014) Eur J Nucl Med Mol Imaging 41, 887-97; Afshar-Oromieh et al. (2015) Eur. J. Nuc.l Med. Mol. Imaging 42, 197-209; Eiber et al. (2015) J Nucl Med 56, 668-74; Eiber et al. (2014) Abdom Imaging; Rowe et al. (2015) J Nucl Med 56, 1003-10). Although there are debatable advantages and disadvantages with respect to which isotope to use for detection with PET, namely 18F vs. 68Ga, the radiometal 68Ga can be produced on-site with a generator, followed by simple synthesis of the radiotracer (Fani et al. (2008) Contrast media & molecular imaging 3, 67-77). 68Ga-1, a radiotracer that employed the DOTA-mono-amide chelator with conjugation to H2N-Lys-(CH2)3-Lys-urea-Glu for targeting to PSMA (FIG. 1) has been previously reported (Banerjee et al. (2010) J Med Chem 53, 5333-41). That chelator has been chosen to make it possible to complex imaging radiometals, such as 68Ga, 86Y, 203Pb, as well as therapeutic radiometal nuclides, such as 177Lu, 90Y, 212Pb or 225Ac, within the same scaffold.
Two 68Ga-based agents have demonstrated excellent clinical results for detection of prostate cancer, namely, 68Ga-DKFZ-PSMA-11 (Glu-urea-Lys-(Ahx)-HBED-CC) and EuK-Sub-kff-68Ga-DOTAGA (68Ga-PSMA I&T) (Herrmann et al. (2015) Journal of Nuclear Medicine; Eder et al. (2012) Bioconjug Chem 23, 688-97; Weineisen et al. (2015) J Nucl Med; Weineisen et al. (2014) EJNMMI Res 4, 63). Those compounds both employ the Glu-Lys-urea-based PSMA-targeted moiety, while 68Ga-DOTA-DUPA-Pep, also recently tested clinically, uses DOTA-monoamide as the chelating agent and Glu-Glu-urea as the PSMA-targeting moiety (Reske et al. (2013) Mol Imaging 40, 969-70). A recent preclinical study also evaluated 68Ga-(CHX-A″-DTPA)-Pep using CHX-A″-DTPA as the chelating agent (Baur et al. (2014) Pharmaceuticals (Basel) 7, 517-29). Among the agents, 68Ga-DKFZ-PSMA-11 has been most widely studied clinically (Afshar-Oromieh et al. (2013) Eur J Nucl Med Mol Imaging 40, 486-95; Afshar-Oromieh et al. (2012) Eur J Nucl Med Mol Imaging 39, 1085-6; Afshar-Oromieh et al. (2013) Eur J Nucl Med Mol Imaging 40, 1629-30; Afshar-Oromieh et al. (2014) Eur J Nucl Med Mol Imaging 41, 887-97; Afshar-Oromieh et al. (2015) Eur. J. Nuc.l Med. Mol. Imaging 42, 197-209; Afshar-Oromieh et al. (2013) Eur J Nucl Med Mol Imaging 40, 971-2; Mottaghy et al. (2015) European Journal of Nuclear Medicine and Molecular Imaging 1-3. The growing number of clinical trials employing 68Ga-based, PSMA-targeted PET provides rationale to investigate structural elements that could promote the least off-target uptake of this class of radiotracers.